Understanding the brainstem network that generates and modulates the respiratory motor pattern is an important goal in physiology and medicine. Disorders that disrupt breathing are associated with the development of pulmonary and systemic hypertension, sudden infant death, learning disabilities, Parkinson's disease and autonomic dysfunction, and other disorders and risks, e.g., stroke and multiple sclerosis. A neural network in the ventrolateral medulla is considered essential for generating the respiratory motor pattern. The circuits used by other brainstem sites to modulate this network are not known. The primary hypothesis of this project is: Peripheral and central chemoreceptors modulate the respiratory motor pattern through a distributed network that includes multifunctional neurons in the "pontine respiratory group" (PRG), the medullary raphe nuclei, and the locus ceruleus. The project has four specific aims: 1. Define functional circuits within the pontine respiratory group (PRG) and between the PRG and the core medullary respiratory network. 2. Define the functional circuits of the PRG and the core medullary respiratory network appropriate for modulation of the respiratory motor pattern during changes in central and peripheral chemoreceptor drive. 3. Define the functional connectivity of raphe neurons that respond to changes in central and peripheral chemoreceptor drive, including functional circuits between the raphe system and the PRG and core medullary networks. 4. Identify functional circuits of locus ceruleus neurons that respond to changes in central and peripheral chemoreceptor drive and their functional connectivity with other modulatory domains and the core medullary respiratory network. The project will use multi-array recordings and computational methods to define functional circuits and their responses during chemoreceptor challenges that alter breathing. The results will lead to new network models of the respiratory brainstem in both normal and pathophysiological conditions.